Biphenylcarboxamides useful as lipid lowering agents

ABSTRACT

Biphenylcarboxamide compounds of formula (I) 
                         
methods for preparing such compounds, pharmaceutical compositions comprising said compounds as well as the use of said compounds as a medicine for the treatment of hyperlipidemia, obesity and type II diabetes.

This application is a divisional application of U.S. patent applicationSer. No. 10/432,404 filed Dec. 24, 2003, now U.S. Pat. No. 7,135,586,which application is the national stage of Application No.PCT/EP01/13316, filed Nov. 15, 2001 which claims priority from EP00204150.7, filed Nov. 21, 2000.

The present invention is concerned with novel biphenylcarboxamidecompounds having apolipoprotein B inhibiting activity and concomitantlipid lowering activity. The invention further relates to methods forpreparing such compounds, pharmaceutical compositions comprising saidcompounds as well as the use of said compounds as a medicine for thetreatment of hyperlipidemia, obesity and type II diabetes.

Obesity is the cause of a myriad of serious health problems like theadult onset of diabetes and heart disease. In addition, the loss ofweight is getting an obsession among an increasing proportion of thehuman population.

The causal relationship between hypercholesterolemia, particularly thatassociated with increased plasma concentrations of low densitylipoproteins (hereinafter referred as LDL) and very low densitylipoproteins (hereinafter referred as VLDL), and prematureatherosclerosis and/or cardiovascular disease is now widely recognized.However, a limited number of drugs are presently available for thetreatment of hyperlipidemia. Drugs primarily used for the management ofhyperlipidemia include bile acid sequestrant resins such ascholestyramine and colestipol, fibric acid derivatives such asbezafibrate, clofibrate, fenofibrate, ciprofibrate and gemfibrozil,nicotinic acid and cholesterol synthesis inhibitors such as HMGCo-enzyme-A reductase inhibitors. The inconvenience of administration (agranular form to be dispersed in water or orange juice) and the majorside-effects (gastrointestinal discomfort and constipation) of bile acidsequestrant resins constitute major drawbacks. Fibric acid derivativesinduce a moderate decrease (by 5 to 25%) of LDL cholesterol (except inhypertriglyceridemic patients in whom initially low levels tend toincrease) and, although usually well tolerated, suffer from side-effectsincluding potentiation of warfarine, pruritus, fatigue, headache,insomnia, painful reversible myopathy and stiffness in large musclegroups, impotency and impaired renal function. Nicotinic acid is apotent lipid lowering agent resulting in a 15 to 40% decrease in LDLcholesterol (and even 45 to 60% when combined with a bile acidsequestrant resin) but with a high incidence of troublesome side-effectsrelated to the drug's associated vasodilatory action, such as headache,flushing, palpitations, tachychardia and occasional syncopes, as well asother side-effects such as gastro-intestinal discomfort, hyperucemia andimpairment of glucose tolerance. Among the family of HMG Co-enzyme-Areductase inhibitors, lovastatin and simvastatin are both inactiveprodrugs containing a lactone ring which is hydrolyzed in the liver toform the corresponding active hydroxy-acid derivative. Inducing areduction of LDL cholesterol by 35 to 45%, they are generally welltolerated with alow incidence of minor side effects. However there stillremains a need for new lipid lowering agents with improved efficiencyand/or acting via other mechanisms than the above mentioned drugs.

Plasma lipoproteins are water-soluble complexes of high molecular weightformed from lipids (cholesterol, triglyceride, phospholipids) andapolipoproteins. Five major classes of lipoproteins that differ in theproportion of lipids and the type of apolipoprotein, all having theirorigin in the liver and/or the intestine, have been defined according totheir density (as measured by ultracentrifugation). They include LDL,VLDL, intermediate density lipoproteins (hereinafter referred as IDL),high density lipoproteins (hereinafter referred as HDL) andchylomicrons. Ten major human plasma apolipoproteins have beenidentified. VLDL, which is secreted by the liver and containsapolipoprotein B (hereinafter referred as Apo-B), undergoes degradationto LDL which transports 60 to 70% of the total serum cholesterol. Apo-Bis also the main protein component of LDL. Increased LDL-cholesterol inserum, due to oversynthesis or decreased metabolism, is causally relatedto atherosclerosis. In contrast high density lipoproteins (hereinafterreferred as HDL), which contain apolipoprotein A1, have a protectiveeffect and are inversely correlated with the risk of a coronary heartdisease. The HDL/LDL ratio is thus a convenient method of assessing theatherogenic potential of an individual's plasma lipid profile.

The two isoforms of apolipoprotein (apo) B, apo B-48 and apo B-100, areimportant proteins in human lipoprotein metabolism. Apo B-48, so namedbecause it appears to be about 48% the size of apo B-100 on sodiumdodecyl sulfate-polyacrylamide gels, is synthesized by the intestine inhumans. Apo B-48 is necessary for the assembly of chylomicrons andtherefore has an obligatory role in the intestinal absorption of dietaryfats. Apo B-100, which is produced in the liver in humans, is requiredfor the synthesis and secretion of VLDL. LDL, which contain about ⅔ ofthe cholesterol in human plasma, are metabolic products of VLDL. ApoB-100 is virtually the only protein component of LDL. Elevatedconcentrations of apo B-100 and LDL cholesterol in plasma are recognizedrisk factors for developing atherosclerotic coronary artery disease.

A large number of genetic and acquired diseases can result inhyperlipidemia. They can be classified into primary and secondaryhyperlipidemic states. The most common causes of the secondaryhyperlipidemias are diabetes mellitus, alcohol abuse, drugs,hypothyroidism, chronic renal failure, nephrotic syndrome, cholestasisand bulimia. Primary hyperlipidemias have also been classified intocommon hypercholesterolaemia, familial combined hyperlipidaemia,familial hypercholesterolaemia, remnant hyperlipidaemia,chylomicronaemia syndrome and familial hyper-triglyceridaemia.

Microsomal triglyceride transfer protein (hereinafter referred as MTP)is known to catalyze the transport of triglyceride and cholesteryl esterby preference to phospholipids such as phosphatidylcholine. It wasdemonstrated by D. Sharp et al., Nature (1993) 365:65 that the defectcausing abetalipoproteinemia is in the MTP gene. This indicates that MTPis required for the synthesis of Apo B-containing lipoproteins such asVLDL, the precursor to LDL. It therefore follows that an MTP inhibitorwould inhibit the synthesis of VLDL and LDL, thereby lowering levels ofVLDL, LDL, cholesterol and triglyceride in humans. MTP inhibitors havebeen reported in Canadian patent application No. 2,091,102 and in WO96/26205. MTP inhibitors belonging to the class of polyarylcarboxamideshave also been reported in U.S. Pat. No. 5,760,246 as well as inWO-96/40640 and WO-98/27979. U.S. Pat. No. 5,968,950 discloses4′-trifluoro-methylbiphenyl-2-carboxylicacid-[2-(2-acetylaminoethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amidehydrochloride as an Apo B secretion/MTP inhibitor. U.S. Pat. No.5,827,875 discloses pyrrolidinyl-substituted fluorenes as inhibitors ofmicrosomal triglyceride transfer protein. U.S. Pat. No. 5,965,577discloses heterocyclic inhibitors of microsomal triglyceride transferprotein.

One of the goals of the present invention is to provide an improvedtreatment for patients suffering from obesity or atherosclerosis,especially coronary atherosclerosis and more generally from disorderswhich are related to atherosclerosis, such as ischaemic heart disease,peripheral vascular disease and cerebral vascular disease. Another goalof the present invention is to cause regression of atherosclerosis andinhibit its clinical consequences, particularly morbidity and mortality.

The present invention is based on the unexpected discovery that a classof novel biphenylcarboxamide compounds is acting as selective MTPinhibitors, i.e. is able to selectively block MTP at the level of thegut wall in mammals, and is therefore a promising candidate as amedicine, namely for the treatment of hyperlipidemia. The presentinvention additionally provides several methods for preparing suchbiphenylcarboxamide compounds, as well as pharmaceutical compositionsincluding such compounds. Furthermore, the invention provides a certainnumber of novel compounds which are useful intermediates for thepreparation of the therapeutically active biphenylcarboxamide compounds,as well as methods for preparing such intermediates. Finally, theinvention provides a method of treatment of a condition selected fromatherosclerosis, pancreatitis, obesity, hypercholesterolemia,hypertriglyceridemia, hyperlipidemia, diabetes and type II diabetes,comprising administering a therapeutically active biphenylcarboxamidecompound to a mammal.

The present invention relates to a family of novel biphenylcarboxamidecompounds of formula (I)

the N-oxides, the pharmaceutically acceptable acid addition salts andthe stereochemically isomeric forms thereof, wherein

-   p¹, p² and p³ are integers each independently from 1 to 3;-   each R¹ is independently selected from hydrogen, C₁₋₄alkyl,    C₁₋₄alkyloxy, halo, hydroxy, mercapto, cyano, nitro, C₁₋₄alkylthio    or polyhaloC₁₋₆alkyl, amino, C₁₋₄alkylamino and di(C₁₋₄alkyl)amino;-   each R² is independently selected from hydrogen, C₁₋₄alkyl,    C₁₋₄alkyloxy, halo, or trifluoromethyl;-   R³ is hydrogen of C₁₋₄alkyl;-   each R⁴ is independently selected from C₁₋₄alkyl, C₁₋₄alkyloxy,    halo, or trifluoromethyl;-   Z is a bivalent radical of formula

-   -   wherein n is an integer from 2 to 4 and the —(CH₂)_(n)— moiety        in radical (a-1) may optionally be substituted with one or two        C₁₋₄alkyl;        -   m and m′ are integers from 1 to 3;        -   R⁵ and R⁶ are each independently selected from hydrogen,            C₁₋₆alkyl or aryl;        -   X¹ and X² are each independently selected from CH, N or an            sp² hybridized carbon atom and in radical (a-1) at least one            of X¹ or X² is N;

-   A represents a bond, C₁₋₆alkanediyl optionally substituted with one    or two groups selected from aryl, heteroaryl and C₃₋₁₀cycloalkyl;

-   B represents hydrogen; C₁₋₁₀alkyl; aryl or heteroaryl each    optionally substituted with a group selected from halo, cyano,    nitro, C₁₋₄alkyloxy, amino, C₁₋₁₀alkylamino, di(C₁₋₁₀alkyl)amino,    C₁₋₁₀acyl, C₁₋₁₀alkylthio, C₁₋₁₀alkoxycarbonyl,    C₁₋₁₀alkylaminocarbonyl and di(C₁₋₁₀alkyl)aminocarbonyl;    arylC₁₋₁₀alkyl; heteroarylC₁₋₁₀alkyl; C₃₋₁₀cycloalkyl;    polyhaloC₁₋₆alkyl; C₃₋₆alkenyl; C₃₋₆alkynyl; NR⁷R⁸; or OR⁹;    -   wherein R⁷ and R⁸ each independently represent hydrogen,        C₁₋₁₀alkyl, aryl or heteroaryl each optionally substituted with        a group selected from halo, cyano, C₁₋₄alkyloxy, amino,        C₁₋₁₀alkylamino, di(C₁₋₁₀alkyl)amino, C₁₋₁₀acyl, C₁₋₁₀alkylthio,        C₁₋₁₀alkylaminocarbonyl and di(C₁₋₁₀alkyl)aminocarbonyl;        arylC₁₋₁₀alkyl, heteroarylC₁₋₁₀alkyl, C₃₋₁₀cycloalkyl,        C₇₋₁₀polycycloalkyl, polyhaloC₁₋₆alkyl, C₃₋₈alkenyl,        C₃₋₈alkynyl, fused benzo-C₅₋₈cycloalkyl, and wherein R⁷ and R⁸        taken together with the nitrogen atom to which they are attached        may form a saturated heterocyclic radical having from 4 to 8        carbon atoms; and    -   wherein R⁹ represents C₁₋₁₀alkyl, aryl or heteroaryl each        optionally substituted with a group selected from halo, cyano,        nitro, C₁₋₄alkyloxy, amino, C₁₋₁₀alkylamino,        di(C₁₋₁₀alkyl)amino, C₁₋₁₀acyl, C₁₋₁₀alkylthio,        C₁₋₁₀alkylaminocarbonyl and di(C₁₋₁₀alkyl)aminocarbonyl;        arylC₁₋₁₀alkyl; heteroarylC₁₋₁₀alkyl; C₃₋₁₀cycloalkyl;        C₇₋₁₀polycycloalkyl; polyhaloC₁₋₆alkyl; C₃₋₈alkenyl;        C₃₋₈alkynyl; or fused benzoC₅₋₈cycloalkyl.

Unless otherwise stated, as used in the foregoing definitions andhereinafter:

-   halo is generic to fluoro, chloro, bromo and iodo;-   C₁₋₄alkyl defines straight and branched chain saturated hydrocarbon    radicals having from 1 to 4 carbon atoms such as, for example,    methyl, ethyl, propyl, n-butyl, 1-methylethyl, 2-methylpropyl,    1,1-dimethylethyl and the like;-   C₁₋₆alkyl is meant to include C₁₋₄alkyl (as hereinabove defined) and    the higher homologues thereof having 5 or 6 carbon atoms, such as    for instance 2-methyl-butyl, n-pentyl, dimethylpropyl, n-hexyl,    2-methylpentyl, 3-methylpentyl and the like;-   C₁₋₁₀alkyl is meant to include C₁₋₆alkyl (as hereinabove defined)    and the higher homologues thereof having 7 to 10 carbon atoms, such    as for instance heptyl, ethylhexyl, octyl, nonyl, decyl and the    like;-   C₃₋₁₀cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl,    cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl;-   polyhaloC₁₋₆alkyl is defined as polyhalosubstituted C₁₋₆alkyl, in    particular C₁₋₆alkyl (as hereinabove defined) substituted with 2 to    13 halogen atoms such as difluoromethyl, trifluoromethyl,    trifluoroethyl, octafluoropentyl and the like;-   aryl is defined as mono- and polyaromatic groups such as phenyl    optionally substituted with a group selected from halo, cyano,    nitro, C₁₋₄alkyloxy, amino, C₁₋₁₀alkylamino, di(C₁₋₁₀alkyl)amino,    C₁₋₁₀acyl, C₁₋₁₀alkylthio, C₁₋₁₀alkoxycarbonyl,    C₁₋₁₀alkylaminocarbonyl and di(C₁₋₁₀alkyl)aminocarbonyl;-   heteroaryl is defined as mono- and polyheteroaromatic groups such as    those including one or more heteroatoms selected from nitrogen,    oxygen, sulfur and phosphorus, in particular pyridinyl, pyrazinyl,    pyrimidinyl, pyridazinyl, triazinyl, triazolyl, imidazolyl,    pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolyl, furanyl,    thienyl and the like, including all possible isomeric forms thereof,    and optionally substituted with a group selected from halo, cyano,    nitro, C₁₋₄alkyloxy, amino, C₁₋₁₀alkylamino, di(C₁₋₁₀alkyl)amino,    C₁₋₁₀acyl, C₁₋₁₀alkylthio, C₁₋₁₀alkoxycarbonyl,    C₁₋₁₀alkylaminocarbonyl and di(C₁₋₁₀alkyl)aminocarbonyl;-   C₃₋₆alkenyl defines straight and branched chain hydrocarbon radicals    containing one double bond and having from 3 to 6 carbon atoms such    as, for example, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl,    3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 2-hexenyl and the like;-   C₃₋₆alkynyl defines straight and branched chain hydrocarbon radicals    containing one triple bond and having from 3 to 6 carbon atoms such    as, for example, 2-propynyl, 3-butynyl, 2-butynyl, 2-pentynyl,    3-pentynyl, 3-methyl-2-butynyl, 3-hexynyl, 2-hexynyl and the like;-   C₄₋₈cycloalkenyl defines cyclic hydrocarbon radicals containing one    double bond and having from 4 to 8 carbon atoms such as, for example    cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,    cyclooctenyl and the like;-   fused benzoC₅₋₈cycloalkyl defines radicals such as, for instance,    indanyl, 1,2,3,4-tetrahydronaphtalenyl, fluorenyl and the like;-   C₇₋₁₀polycycloalkyl defines radicals having from 7 to 10 carbon    atoms such as, for instance, norbornyl;-   C₁₋₆alkylamino defines primary amino radicals having from 1 to 6    carbon atoms such as, for example, methylamino, ethylamino,    propylamino, isopropylamino, butylamino, isobutylamino and the like;-   di(C₁₋₆alkyl)amino defines secondary amino radicals having from 1 to    6 carbon atoms such as, for example, dimethylamino, diethylamino,    dipropylamino, diisopropylamino, N-methyl-N′-ethylamino,    N-ethyl-N′-propylamino and the like;-   C₁₋₆alkylthio defines a C₁₋₆alkyl group attached to a sulfur atom,    such as methylthio, ethylthio, propylthio, isopropylthio, butylthio    and the like;-   C₁₋₆acyl defines a C₁₋₆alkyl group attached to a carbonyl group such    as, for instance acetyl, propionyl, butyryl, isobutyryl and the    like.

Examples of the bivalent radical Z wherein one of X¹ or X² represents ansp² hybridized carbon atom are:

The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid addition salt forms which the compounds of formula (I) are able toform. The pharmaceutically acceptable acid addition salts canconveniently be obtained by treating the base form with such appropriateacid. Appropriate acids comprise, for example, inorganic acids such ashydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric,nitric, phosphoric and the like acids; or organic acids such as, forexample, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e.ethanedioic), malonic, succinic (i.e. butane-dioic acid), maleic,fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.

The term addition salt as used hereinabove also comprises the solvateswhich the compounds of formula (I) as well as the salts thereof, areable to form. Such solvates are for example hydrates, alcoholates andthe like.

The N-oxide forms of the compounds of formula (I), which may be preparedin art-known manners, are meant to comprise those compounds of formula(I) wherein a nitrogen atom is oxidized to the N-oxide.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible isomeric forms which the compounds of formula (I) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure. More inparticular, stereogenic centers may have the R- or S-configuration;substituents on bivalent cyclic (partially) saturated radicals may haveeither the cis- or trans-configuration. Unless otherwise mentioned orindicated, the chemical designation of compounds denotes the mixture ofall possible stereoisomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure. The sameapplies to the intermediates as described herein, used to prepare endproducts of formula (I).

The terms cis and trans are used herein in accordance with ChemicalAbstracts nomenclature and refer to the position of the substituents ona ring moiety.

The absolute stereochemical configuration of the biphenylcarboxamidecompounds of formula (I) and of the intermediates used in theirpreparation may easily be determined by those skilled in the art whileusing well-known methods such as, for example, X-ray diffraction.

Furthermore, some biphenylcarboxamide compounds of formula (I) and someof the intermediates used in their preparation may exhibit polymorphism.It is to be understood that the present invention encompasses anypolymorphic forms possessing properties useful in the treatment of theconditions noted hereinabove.

A group of interesting compounds consists of those compounds of formula(I) wherein one or more of the following restrictions apply:

-   a) R¹ is hydrogen or trifluoromethyl;-   b) R² is hydrogen;-   c) R³ is hydrogen;-   d) R⁴ is hydrogen;-   e) p¹ is 1;-   f) p² is 1;-   g) p³ is 1;-   h) Z is a bivalent radical of formula (a-1) wherein X¹ and X² are    each nitrogen;-   i) Z is a bivalent radical of formula (a-2) wherein X¹ is nitrogen    and m and m′ are the integer 1;-   j) Z is a bivalent radical of formula (a-2) wherein X¹ is nitrogen,    m is the integer 2 and m′ is the integer 1;-   k) Z is a bivalent radical of formula (a-3) wherein X¹ is nitrogen    and m and m′ are the integer 1;-   l) Z is a bivalent radical of formula (a-3) wherein X¹ is nitrogen,    m is the integer 2 and m′ is the integer 1;-   m) Z is the bivalent radical of formula (a-4) wherein m is the    integer 2 and m′ is the integer 1;-   n) R⁵ and R⁶ are each independently hydrogen or methyl;-   o) the bivalent radical A is C₁₋₆alkanediyl substituted with one    aryl group, in particular A is a methylene group substituted with    phenyl;-   p) B is C₁₋₄alkyloxy, or C₁₋₁₀alkylamino.

More interesting compounds are those compounds of formula (I) wherein R¹is hydrogen or trifluoromethyl; R², R³ and R⁴ are hydrogen; and Z is abivalent radical of formula (a-1) wherein X¹ and X² are each nitrogen, nis the integer 2, and R⁵ and R⁶ are each independently hydrogen ormethyl.

Other more interesting compounds are those compounds of formula (I)wherein R¹ is hydrogen or trifluoromethyl; R², R³ and R⁴ are hydrogen;and Z is a bivalent radical of formula (a-2) or (a-3) wherein X¹ isnitrogen, m and m′ are the integer 1, and R⁵ and R⁶ are eachindependently hydrogen or methyl.

Still other more interesting compounds are those compounds of formula(I) wherein R¹ is hydrogen or trifluoromethyl; R², R³ and R⁴ arehydrogen; and Z is a bivalent radical of formula (a-2) or (a-3) whereinX¹ is nitrogen, m is the integer 2, m′ is the integer 1, and R⁵ and R⁶are each independently hydrogen or methyl.

Yet other more interesting compounds are those compounds of formula (I)wherein R¹ is hydrogen or trifluoromethyl; R², R³ and R⁴ are hydrogen;and Z is a bivalent radical of formula (a-4) wherein m is the integer 2and m′ is the integer 1, and R⁵ and R⁶ are each independently hydrogenor methyl.

One advantage of the present invention is the easiness with which thecompounds of formula (I) can be manufactured by a high number ofdifferent processes. Some of these processes will now be described indetails, without pretending to provide an exhaustive list of the methodsfor preparing the said compounds.

A first process for preparing a biphenylcarboxamide compound accordingto this invention is a process wherein an intermediate phenylene aminehaving the formula

wherein B, A, Z and R⁴ are as defined in formula (I), is reacted with abiphenyl-carboxylic acid or halide having the formula (III),

wherein R¹ and R² are as defined in formula (I) and Y¹ is selected fromhydroxy and halo, in at least one reaction-inert solvent and optionallyin the presence of a suitable base, the said process further optionallycomprising converting a compound of formula (I) into an addition saltthereof, and/or preparing stereochemically isomeric forms thereof. Incase Y¹ is hydroxy, it may be convenient to activate thebiphenylcarboxylic acid of formula (III) by adding an effective amountof a reaction promoter. Non-limiting examples of such reaction promotersinclude carbonyldiimidazole, diimides such asN,N′-dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and functionalderivatives thereof. For this type of acylation procedure, it ispreferred to use a polar aprotic solvent such as, for instance,methylene chloride. Suitable bases for carrying out this first processinclude tertiary amines such as triethylamine, triisopropylamine and thelike. Suitable temperatures for carrying out the first process of theinvention typically range from about 20° C. to about 140° C., dependingon the particular solvent used, and will most often be the boilingtemperature of the said solvent.

A second process for preparing a biphenylcarboxamide compound of theinvention is a process wherein an intermediate having the formula (IV)

wherein R¹, R², R³, R⁴, A and Z are as defined in formula (I) and Y² isselected from halo and hydroxy, is reacted with an intermediate (V) ofthe formula B-H, wherein B is NR⁷R⁸ or OR⁹ and R⁷, R⁸ and R⁹ are asdefined in formula (I), in at least one reaction-inert solvent andoptionally in the presence of at least one suitable coupling reagentand/or a suitable base, the said process further optionally comprisingconverting a compound of formula (I) into an addition salt thereof,and/or preparing stereochemically isomeric forms thereof. In case Y² ishydroxy, it may be convenient to activate the carboxylic acid of formula(IV) by adding an effective amount of a reaction promoter. Non-limitingexamples of such reaction promoters include carbonyldiimidazole,diimides such as N,N′-dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbo-diimide, and functionalderivatives thereof. In case a chirally pure reactant of formula (V) isused, a fast and enantiomerization-free reaction of the intermediate offormula (IV) with the said intermediate (V) may be performed in thefurther presence of an effective amount of a compound such ashydroxybenzotriazole, benzotriazolyloxytris (dimethylamino)phosphoniumhexafluorophosphate, tetrapyrrolidinophosphonium hexafluorophosphate,bromotripyrrolidinophosphonium hexafluorophosphate, or a functionalderivative thereof, such as disclosed by D. Hudson, J. Org. Chem.(1988), 53:617. In case Y² is hydroxy and B is OR⁹, then theesterification reaction may conveniently be performed in the presence ofan effective amount of an acid such as sulfuric acid and the like.

A third process for preparing a biphenylcarboxamide compound accordingto this invention is a process wherein an intermediate having theformula (VI)

wherein R¹, R², R³, and R⁴ are as defined in formula (I) and Y³ isselected from halo, B(OH)₂, alkylboronates and cyclic analogues thereof,is reacted with a reactant having the formula (VII)

wherein B, A and Z are as defined in formula (I), in at least onereaction-inert solvent and optionally in the presence of at least onetransition metal coupling reagent and/or at least one suitable ligand,the said process further optionally comprising converting a compound offormula (I) into an addition salt thereof, and/or preparingstereochemically isomeric forms thereof. This type of reaction beingknown in the art as the Buchwaldt reaction, reference to the applicablemetal coupling reagents and/or suitable ligands, e.g. palladiumcompounds such as palladium tetra(triphenyl-phosphine),tris(dibenzylidene-acetone dipalladium,2,2′-bis(diphenylphosphino)-1,1′-binaphtyl and the like, may be foundfor instance in Tetrahedron Letters (1996) 37(40) 7181-7184 and J. Am.Chem. Soc. (1996) 118:7216. If Y³ is B(OH)₂, an alkylboronate or acyclic analogue thereof, then cupric acetate should be used as thecoupling reagent, according to Tetrahedron Letters (1998) 39:2933-6.

The compounds of formula (I) can conveniently be prepared using solidphase synthesis techniques as depicted in Scheme 1 below. In general,solid phase synthesis involves reacting an intermediate in a synthesiswith a polymer support. This polymer supported intermediate can then becarried on through a number of synthetic steps. After each step,impurities are removed by filtering the resin and washing it numeroustimes with various solvents. At each step the resin can be split up toreact with various intermediates in the next step thus allowing for thesynthesis of a large number of compounds. After the last step in theprocedure the resin is treated with a reagent or process to cleave theresin from the sample. More detailed explanation of the techniques usedin solid phase chemistry are described in for example “The CombinatorialIndex” (B. Bunin, Academic Press) and Novabiochem's 1999 Catalogue &Peptide Synthesis Handbook (Novabiochem AG, Switzerland) bothincorporated herein by reference.

The abreviations used in Scheme 1 are explained in the ExperimentalPart. The substituents R¹, R², R³, R⁴, A, B, and Z are as defined forcompounds of formula (I). PG represents a protecting group such as, e.g.t-butoxycarbonyl, C₁₋₆alkyloxycarbonyl, phenylmethyloxycarbonyl and thelike.

The compounds of formula (I) as prepared in the hereinabove describedprocesses may be synthesized in the form of racemic mixtures ofenantiomers which can be separated from one another following art-knownresolution procedures. The racemic compounds of formula (I) may beconverted into the corresponding diastereomeric salt forms by reactionwith a suitable chiral acid. Said diastereomeric salt forms aresubsequently separated, for example, by selective or fractionalcrystallization and the enantiomers are liberated therefrom by alkali.An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) involves liquid chromatography using a chiralstationary phase. Said pure stereochemically isomeric forms may also bederived from the corresponding pure stereochemically isomeric forms ofthe appropriate starting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

The biphenylcarboxamide compounds of formula (I), the N-oxide forms, thepharmaceutically acceptable salts and stereoisomeric forms thereofpossess favourable apolipoprotein B inhibiting activity and concomitantlipid lowering activity. Therefore the present compounds are useful as amedicine especially in a method of treating patients suffering fromhyperlipidemia, obesity, atherosclerosis or type II diabetes. Inparticular the present compounds may be used for the manufacture of amedicine for treating disorders caused by an excess of very low densitylipoproteins (VLDL) or low density lipoproteins (LDL), and especiallydisorders caused by the cholesterol associated with said VLDL and LDL.

The causal relationship between hypercholesterolemia—particularly thatassociated with increased plasma concentrations of low densitylipoproteins (LDL) and very low density lipoproteins (VLDL)—andpremature atherosclerosis and cardiovascular disease is wellestablished. VLDL is secreted by the liver and contains apolipoprotein B(apo-B); these particles undergo degradation in the circulation to LDL,which transports about 60 to 70% of the total serum cholesterol. Apo-Bis also the principal protein component of LDL. IncreasedLDL-cholesterol in serum, due to oversynthesis or decreased metabolism,is causally related to atherosclerosis. In contrast, high densitylipoproteins (HDL) which contain apolipoprotein A1, have a protectiveeffect and are inversely correlated with risk of coronary heart disease.The HDL/LDL ratio is thus a convenient method of assessing theatherogenic potential of an individual's plasma lipid profile.

The principal mechanism of action of the compounds of formula (I)appears to involve inhibition of MTP (microsomial triglyceride transferprotein) activity in hepatocytes and intestinal epithelial cells,resulting in decreased VLDL and chylomicron production, respectively.This is a novel and innovative approach to hyperlipidemia, and isexpected to lower LDL-cholesterol and triglycerides through reducedhepatic production of VLDL and intestinal production of chylomicrons.

A large number of genetic and acquired diseases can result inhyperlipidemia. They can be classified into primary and secondaryhyperlipidemic states. The most common causes of the secondaryhyperlipidemias are diabetes mellitus, alcohol abuse, drugs,hypothyroidism, chronic renal failure, nephrotic syndrome, cholestasisand bulimia. Primary hyperlipidemias are common hypercholesterolaemia,familial combined hyperlipidaemia, familial hypercholesterolaemia,remnant hyperlipidaemia, chylomicronaemia syndrome, familialhypertriglyceridaemia. The present compounds may also be used to preventor treat patients suffering from obesitas or from atherosclerosis,especially coronary atherosclerosis and more in general disorders whichare related to atherosclerosis, such as ischaemic heart disease,peripheral vascular disease, cerebral vascular disease. The presentcompounds may cause regression of atherosclerosis and inhibit theclinical consequences of atherosclerosis, particularly morbidity andmortality.

In view of the utility of the compounds of formula (I), it follows thatthe present invention also provides a method of treating warm-bloodedanimals, including humans, (generally called herein patients) sufferingfrom disorders caused by an excess of very low density lipoproteins(VLDL) or low density lipoproteins (LDL), and especially disorderscaused by the cholesterol associated with said VLDL and LDL.Consequently a method of treatment is provided for relieving patientssuffering from conditions, such as, for example, hyperlipidemia,obesity, atherosclerosis or type II diabetes.

Apo B-48, synthetized by the intestine, is necessary for the assembly ofchylomicrons and therefore has an obligatory role in the intestinalabsorption of dietary fats. The present invention providesbiphenylcarboxamide compounds which are acting as selective MTPinhibitors at the level of the gut wall.

Additionally the present invention provides pharmaceutical compositionscomprising at least one pharmaceutically acceptable carrier and atherapeutically effective amount of a biphenylcarboxamide compoundhaving the formula (I).

In order to prepare the pharmaceutical compositions of this invention,an effective amount of the particular compound, in base or addition saltform, as the active ingredient is combined in intimate admixture with atleast one pharmaceutically acceptable carrier, which carrier may take awide variety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for oral administration,rectal administration, percutaneous administration or parenteralinjection.

For example in preparing the compositions in oral dosage form, any ofthe usual liquid pharmaceutical carriers may be employed, such as forinstance water, glycols, oils, alcohols and the like in the case of oralliquid preparations such as suspensions, syrups, elixirs and solutions;or solid pharmaceutical carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their easyadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral injection compositions, thepharmaceutical carrier will mainly comprise sterile water, althoughother ingredients may be included in order to improve solubility of theactive ingredient. Injectable solutions may be prepared for instance byusing a pharmaceutical carrier comprising a saline solution, a glucosesolution or a mixture of both. Injectable suspensions may also beprepared by using appropriate liquid carriers, suspending agents and thelike. In compositions suitable for percutaneous administration, thepharmaceutical carrier may optionally comprise a penetration enhancingagent and/or a suitable wetting agent, optionally combined with minorproportions of suitable additives which do not cause a significantdeleterious effect to the skin. Said additives may be selected in orderto facilitate administration of the active ingredient to the skin and/orbe helpful for preparing the desired compositions. These topicalcompositions may be administered in various ways, e.g., as a transdermalpatch, a spot-on or an ointment. Addition salts of the compounds offormula (I), due to their increased water solubility over thecorresponding base form, are obviously more suitable in the preparationof aqueous compositions.

It is especially advantageous to formulate the pharmaceuticalcompositions of the invention in dosage unit form for ease ofadministration and uniformity of dosage. “Dosage unit form” as usedherein refers to physically discrete units suitable as unitary dosages,each unit containing a predetermined amount of active ingredientcalculated to produce the desired therapeutic effect in association withthe required pharmaceutical carrier. Examples of such dosage unit formsare tablets (including scored or coated tablets), capsules, pills,powder packets, wafers, injectable solutions or suspensions,teaspoonfuls, tablespoonfuls and the like, and segregated multiplesthereof.

For oral administration, the pharmaceutical compositions of the presentinvention may take the form of solid dose forms, for example, tablets(both swallowable and chewable forms), capsules or gelcaps, prepared byconventional means with pharmaceutically acceptable excipients andcarriers such as binding agents (e.g. pregelatinised maize starch,polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like),fillers (e.g. lactose, microcrystalline cellulose, calcium phosphate andthe like), lubricants (e.g. magnesium stearate, talc, silica and thelike), disintegrating agents (e.g. potato starch, sodium starchglycollate and the like), wetting agents (e.g. sodium laurylsulphate)and the like. Such tablets may also be coated by methods well known inthe art.

Liquid preparations for oral administration may take the form of e.g.solutions, syrups or suspensions, or they may be formulated as a dryproduct for admixture with water and/or another suitable liquid carrierbefore use. Such liquid preparations may be prepared by conventionalmeans, optionally with other pharmaceutically acceptable additives suchas suspending agents (e.g. sorbitol syrup, methylcellulose,hydroxypropylmethylcellulose or hydrogenated edible fats), emulsifyingagents (e.g. lecithin or acacia), non-aqueous carriers (e.g. almond oil,oily esters or ethyl alcohol), sweeteners, flavours, masking agents andpreservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).

Pharmaceutically acceptable sweeteners useful in the pharmaceuticalcompositions of the invention comprise preferably at least one intensesweetener such as aspartame, acesulfame potassium, sodium cyclamate,alitame, a dihydrochalcone sweetener, monellin, stevioside sucralose(4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose) or, preferably,saccharin, sodium or calcium saccharin, and optionally at least one bulksweetener such as sorbitol, mannitol, fructose, sucrose, maltose,isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey.Intense sweeteners are conveniently used in low concentrations. Forexample, in the case of sodium saccharin, the said concentration mayrange from about 0.04% to 0.1% (weight/volume) of the final formulation.The bulk sweetener can effectively be used in larger concentrationsranging from about 10% to about 35%, preferably from about 10% to 15%(weight/volume).

The pharmaceutically acceptable flavours which can mask the bittertasting ingredients in the low-dosage formulations are preferably fruitflavours such as cherry, raspberry, black currant or strawberry flavour.A combination of two flavours may yield very good results. In thehigh-dosage formulations, stronger pharmaceutically acceptable flavoursmay be required such as Caramel Chocolate, Mint Cool, Fantasy and thelike. Each flavour may be present in the final composition in aconcentration ranging from about 0.05% to 1% (weight/volume).Combinations of said strong flavours are advantageously used. Preferablya flavour is used that does not undergo any change or loss of tasteand/or color under the circumstances of the formulation.

The biphenylcarboxamide compounds of this invention may be formulatedfor parenteral administration by injection, conveniently intravenous,intra-muscular or subcutaneous injection, for example by bolus injectionor continuous intravenous infusion. Formulations for injection may bepresented in unit dosage form, e.g. in ampoules or multi-dosecontainers, including an added preservative. They may take such forms assuspensions, solutions or emulsions in oily or aqueous vehicles, and maycontain formulating agents such as isotonizing, suspending, stabilizingand/or dispersing agents. Alternatively, the active ingredient may bepresent in powder form for mixing with a suitable vehicle, e.g. sterilepyrogen-free water, before use. The biphenylcarboxamide compounds ofthis invention may also be formulated in rectal compositions such assuppositories or retention enemas, e.g. containing conventionalsuppository bases such as cocoa butter and/or other glycerides.

The biphenylcarboxamide compounds of this invention may be used inconjunction with other pharmaceutical agents, in particular thepharmaceutical compositions of the present invention may furthercomprise at least one additional lipid-lowering agent, thus leading to aso-called combination lipid-lowering therapy. The said additionallipid-lowering agent may be, for instance, a known drug conventionallyused for the management of hyperlipidaemia such as e.g. a bile acidsequestrant resin, a fibric acid derivative or nicotinic acid aspreviously mentioned in the background of the invention. Suitableadditional lipid-lowering agents also include other cholesterolbiosynthesis inhibitors and cholesterol absorption inhibitors,especially HMG-CoA reductase inhibitors and HMG-CoA synthase inhibitors,HMG-CoA reductase gene expression inhibitors, CETP inhibitors, ACATinhibitors, squalene synthetase inhibitors and the like.

Any HMG-CoA reductase inhibitor may be used as the second compound inthe combination therapy aspect of this invention. The term “HMG-CoAreductase inhibitor” as used herein, unless otherwise stated, refers toa compound which inhibits the biotransformation ofhydroxymethylglutaryl-coenzyme A to mevalonic acid as catalyzed by theenzyme HMG-CoA reductase. Such inhibition may be determined readily byone skilled in the art according to standard assays, i.e. Methods ofEnzymology (1981) 71:455-509. Exemplary compounds are described e.g. inU.S. Pat. No. 4,231,938 (including lovastatin), U.S. Pat. No. 4,444,784(including simvastatin), U.S. Pat. No. 4,739,073 (includingfluvastatin), U.S. Pat. No. 4,346,227 (including pravastatin),EP-A-491,226 (including rivastatin) and U.S. Pat. No. 4,647,576(including atorvastatin).

Any HMG-CoA synthase inhibitor may be used as the second compound in thecombination therapy aspect of this invention. The term “HMG-CoA synthaseinhibitor” as used herein, unless otherwise stated, refers to a compoundwhich inhibits the biosynthesis of hydroxymethylglutaryl-coenzyme A fromacetyl-coenzyme A and acetoacetyl-coenzyme A, catalyzed by the enzymeHMG-CoA synthase. Such inhibition may be determined readily by oneskilled in the art according to standard assays, i.e. Methods ofEnzymology (1985) 110:19-26. Exemplary compounds are described e.g. inU.S. Pat. No. 5,120,729 relating to beta-lactam derivatives, U.S. Pat.No. 5,064,856 relating to spiro-lactone derivatives and U.S. Pat. No.4,847,271 relating to oxetane compounds.

Any HMG-CoA reductase gene expression inhibitor may be used as thesecond compound in the combination therapy aspect of this invention.These agents may be HMG-CoA reductase trancription inhibitors that blockthe transcription of DNA or translation inhibitors that preventtranslation of mRNA coding for HMG-CoA reductase into protein. Suchinhibitors may either affect trancription or translation directly or maybe biotransformed into compounds having the above-mentioned attributesby one or more enzymes in the cholesterol biosynthetic cascade or maylead to accumulation of a metabolite having the above-mentionedactivities. Such regulation may be determined readily by one skilled inthe art according to standard assays, i.e. Methods of Enzymology (1985)110:9-19. Exemplary compounds are described e.g. in U.S. Pat. No.5,041,432 and E. I. Mercer, Prog. Lip. Res. (1993) 32:357-416.

Any CETP inhibitor may be used as the second compound in the combinationtherapy aspect of this invention. The term “CETP inhibitor” as usedherein, unless otherwise stated, refers to a compound which inhibits thecholesteryl ester transfer protein (CETP) mediated transport of variouscholesteryl esters and triglycerides from HDL to LDL and VLDL. Exemplarycompounds are described e.g. in U.S. Pat. No. 5,512,548, in J. Antibiot.(1996) 49(8):815-816 and Bioorg. Med. Chem. Lett. (1996) 6:1951-1954.

Any ACAT inhibitor may be used as the second compound in the combinationtherapy aspect of this invention. The term “ACAT inhibitor” as usedherein, unless otherwise stated, refers to a compound which inhibits theintracellular esterification of dietary cholesterol by the enzyme acylCoA:cholesterol acyltransferase. Such inhibition may be determinedreadily by one skilled in the art according to standard assays, i.e. themethod of Heider et al., Journal of Lipid Research (1983) 24:1127.Exemplary compounds are described e.g. in U.S. Pat. No. 5,510,379, in WO96/26948 and WO 96/10559.

Any squalene synthetase inhibitor may be used as the second compound inthe combination therapy aspect of this invention. The term “squalenesynthetase inhibitor” as used herein, unless otherwise stated, refers toa compound which inhibits the condensation of two molecules offarnesylpyrophosphate to form squalene, catalyzed by the enzyme squalenesynthetase. Such inhibition may be determined readily by one skilled inthe art according to standard methods, i.e. Methods of Enzymology (1985)110:359-373. Exemplary compounds are described e.g. in EP-A-567,026, inEP-A-645,378 and in EP-A-645,377.

Those of skill in the treatment of hyperlipidemia will easily determinethe therapeutically effective amount of a biphenylcarboxamide compoundof this invention from the test results presented hereinafter. Ingeneral it is contemplated that a therapeutically effective dose will befrom about 0.001 mg/kg to about 5 mg/kg of body weight, more preferablyfrom about 0.01 mg/kg to about 0.5 mg/kg of body weight of the patientto be treated. It may be appropriate to administer the therapeuticallyeffective dose in the form of two or more sub-doses at appropriateintervals throughout the day. Said sub-doses may be formulated as unitdosage forms, for example each containing from about 0.1 mg to about 350mg, more particularly from about 1 to about 200 mg, of the activeingredient per unit dosage form.

The exact dosage and frequency of administration depends on theparticular biphenylcarboxamide compound of formula (I) used, theparticular condition being treated, the severity of the condition beingtreated, the age, weight and general physical condition of theparticular patient as well as the other medication (including theabove-mentioned additional lipid-lowering agents), the patient may betaking, as is well known to those skilled in the art. Furthermore, saideffective daily amount may be lowered or increased depending on theresponse of the treated patient and/or depending on the evaluation ofthe physician prescribing the biphenylcarboxamide compounds of theinstant invention. The effective daily amount ranges mentionedhereinabove are therefore only guidelines.

Experimental Part

In the procedures described hereinafter the following abbreviations wereused: “ACN” stands for acetonitrile; “THF” stands for tetrahydrofuran;“DCM” stands for dichloromethane; “DIPE” stands for diisopropylether;“DMF” means N,N-dimethyl-formamide; “NMP” means N-methyl-2-pyrrolidone;“TFA” means trifluoroacetic acid; “TIS” means triisopropylsilane;“DIPEA” means diisopropylethylamine; “MIK” means methyl isobutyl ketone;“BINAP” means 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; and “TMSOTf”means trimethylsilyl triflate.

A. Synthesis of the Intermediates

For the combinatorial approach a number intermediate resins wereprepared starting from a commercially available resin:

EXAMPLE A.1

A mixture of Novabiochem 01-64-0261 commercial resin (25.1 g),4-bromoaniline (24 g) and titanium (IV) isopropoxide (41 ml) in DCM (400ml) was stirred gently for one hour at room temperature. Sodiumtriacetoxyborohydride (30 g) was added and the reaction mixture wasstirred overnight at room temperature. Methanol (50 ml) was added andthe mixture was stirred for one hour, then filtered, washed once withDCM, once with methanol, then once with DCM (200 ml)+DIPEA (20 ml),washed three times with firstly DCM, followed secondly by methanol, thendried, yielding 29.28 g of a resin identified as resin(1) in scheme 2,which is used in the next reaction step without further purification.

EXAMPLE A.2

2-Phenyl benzoic acid (8.3 g) was dissolved in DCM (100 ml). Thionylchloride (10 g) was added. DMF (10 drops) was added and the mixture wasstirred and refluxed for one hour. The solvent was evaporated. DCM(three times 50 ml) was added to the residue and the solvent wasevaporated. The residue was dissolved in DCM (50 ml). This solution wasadded to a mixture of the resin (1) of example A.1 (14.64 g), DIPEA (24ml) and 4-dimethylaminopyridine (hereinafter referred as DMAP) (0.5 g)in DCM (150 ml). The reaction mixture was shaken overnight at roomtemperature, then filtered and the filter residue was washed with 100 mlDMF+20 ml DIPEA, then with methanol, water, DCM, methanol, DCM andmethanol, and dried, yielding 15.73 g of a resin identified as resin(2-a) in scheme 2.

EXAMPLE A.3

4′-(Trifluoromethyl)-2-biphenyl carboxylic acid (14.64 g) was dissolvedin DCM (100 ml). DMF (1 ml) was added. Thionyl chloride (10 g) was addedand the mixture was stirred and refluxed for one hour. The solvent wasevaporated. DCM (twice 50 ml) was added, then the solvent wasevaporated. The residue was dissolved in DCM (50 ml). This solution wasadded to a mixture of the resin (1) of example A.1 (14.64 g), DIPEA (24ml) and DMAP (0.5 g) in DCM (150 ml). The reaction mixture was shakenfor four hours at room temperature then filtered and the filter residuewas washed with 100 ml DMF+20 ml DIPEA, then washed three times firtstlywith DCM and secondly with methanol, and finally dried. This reactionproduct was reacted once more with half the initial quantities of4′-(trifluoromethyl)-2-biphenyl carboxylic acid, thionyl chloride, DIPEAand DMAP. The reaction mixture was shaken overnight at room temperature,then filtered, and the filter residue was shaken with DMF+20 ml DIPEA,then methanol, water, methanol, DCM, methanol, DCM+methanol, then dried,yielding 17.48 g of a resin identified as resin (2-b) in scheme 2.

EXAMPLE A.4

a) A solution of 4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carbonylchloride (0.019 mol) in DCM (50 ml) was added slowly at 5° C. to amixture of 1-amino-4-iodo-benzene (0.017 mol) and triethylamine (0.026mol) in DCM (40 ml). The mixture was stirred at room temperature for 1hour, then washed with HCl 1N, then with K₂CO₃ 10%. The organic layerwas separated, dried, filtered, and the solvent was evaporated. Theresidue was crystallized from DIPE. The precipitate was filtered off anddried, yielding 6.1 g ofN-(4-iodophenyl)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide(intermediate 1; mp. 147° C.).

b) A mixture of intermediate (1) (0.012 mol), N-allyl-phthalimide (0.012mol), palladium(II) acetate (0.001 mol) and triethylamine (0.024 mol)was stirred at 100° C. for 12 hours in a bomber, then dissolved in DCMand washed with K₂CO₃ 10%. The organic layer was separated, dried,filtered, and the solvent was evaporated. The residue was crystallizedfrom ACN. The precipitate was filtered off and dried, yielding 3.2 g ofN-[4-[(1E)-3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-propenyl]phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide(intermediate 2; mp. 190° C.).

c) A mixture of intermediate (2) (0.005 mol) and an aqueous hydrazinesolution (0.005 mol) in ethanol (30 ml) was stirred and refluxed for 2hours. The precipitate was filtered and washed with ethanol. Water wasadded. The suspension was basified with NaOH and filtered over celite.Celite was washed with ethyl acetate. The filtrate was extracted withethyl acetate and washed with K₂CO₃, then with NaCl. The organic layerwas separated, dried, filtered, and the solvent was evaporated. Theresidue was crystallized from ACN. The precipitate was filtered off anddried, yielding 2.5 g ofN-[4-[(1E)-3-amino-1-propenyl]phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide(intermediate 3; mp. 190° C.).

B. Synthesis of the Final Compounds

EXAMPLE B.1

A suspension of BINAP (0.00014 mol) in NMP (1 ml) was added to resin(2-b) (0.00014 mol) and sodium tert-butoxide (0.00252 mol).1,2-Diaminoethane (0.0021 mol) in NMP (2 ml) was added and the mixturewas stirred under argon. Pd₂(dba)₃ (0.000028 mol) in NMP (1 ml) wasadded and the reaction mixture was shaken for 19 hours at 105° C. Themixture was cooled, filtered and the filter residue was washed with DMF,water, DMF (3×), water (3×), DMF (3×), CH₃OH (3×), DCM (3×), CH₃OH (3×)and NMP (2×). NMP (3 ml) was added. Methyl 2-bromo-2-phenylacetate(0.0007 mol) in NMP (1 ml) was added. DIPEA (0.3 ml) was added and thereaction mixture was shaken for 18 hours at room temperature. Thereaction mixture was filtered, washed with DMF and water, then with DMF(3×), water (3×), DMF (3×), CH₃OH (3×), DCM (3×), CH₃OH (3×) and DCM(3×). A solution of TFA/TIS/DCM (49:2:49) (4 ml) was added and themixture was shaken for one hour at room temperature. The mixture wasfiltered and more TFA/TIS/DCM (49:2:49) (1.5 ml) was added. The mixturewas shaken for 15 minutes, filtered, washed with DCM (2 ml), then thefiltrates were blown dry under nitrogen. The residue was purified byHPLC over Purospher Star RP-18 (20 g, 5 μm; eluent: ((0.5% NH₄OAc inH₂O)/CH₃CN 90/10)/CH₃OH/CH₃CN (0 min) 75/25/0, (10.00 min) 0/50/50,(16.00 min) 0/0/100, (18.10-20 min) 75/25/0). The desired fractions werecollected and the organic solvent was evaporated. The aqueousconcentrate was treated with an aqueous Na₂CO₃ solution, then extractedwith DCM. The extract was separated through Extrelut and the filtrateswere blown dry under nitrogen at 50° C. The residue was dried further(vacuum, 50° C.), yielding 0.006 g of compound 1.

Compounds identified as No. 2 to No. 29 in the following table F-1 weresimilarly prepared while using the same experimental procedure andreplacing 1,2-diaminoethane by the appropriate reactive diamine.

EXAMPLE B.2

NMP (2 ml) was added to resin (2-a) (0.00014 mol). BINAP (0.00014 mol)and sodium tert-butoxide (0.00252 mol) were added. 1,2-Diaminoethane(0.0021 mol) in NMP (1 ml) was added and the mixture was shaken for 1hour under argon. Pd₂(dba)₃ (0.000028 mol) in NMP (1 ml) was added andthe reaction mixture was shaken for 18 hours at 105° C. The mixture wascooled, filtered and the filter residue was washed with DMF-water 50-50,DMF (3×), water (3×), DMF (3×), CH₃OH (3×), DCM (3×), CH₃OH (3×) and NMP(2×). NMP (3 ml) was added. Methyl 2-bromo-2-phenylacetate (0.0007 mol)in NMP (1 ml) was added. DIPEA (0.300 ml) was added and the mixture wasshaken for 18 hours at room temperature. The mixture was filtered,washed with DMF and water, washed with DMF (3×), water (3×), DMF (3×),CH₃OH (3×), DCM (3×), CH₃OH (3×), DCM (3×). TFA/TIS/DCM (49:2:49) (4 ml)was added and the mixture was shaken for 2 hours at room temperature,then filtered. More TFA/TIS/DCM (49:2:49) (2 ml) was added and thereaction mixture was shaken for 15 minutes, then filtered. The filterresidue was washed with DCM (2 ml), then the filtrates were blown dryunder nitrogen. The residue was purified by HPLC over Purospher StarRP-18 (20 g, 5 μm; eluent: ((0.5% NH₄OAc in H₂O)/CH₃CN90/10)/CH₃OH/CH₃CN (0 min) 75/25/0, (10.00 min) 0/50/50, (16.00 min)0/0/100, (18.10-20 min) 75/25/0). The desired fractions were collectedand the organic solvent was evaporated. The aqueous concentrate wastreated with an aqueous Na₂CO₃ solution, then extracted with DCM. Theextract was separated and the filtrates were blown dry under nitrogen at50° C. The residue was dried further (vacuum, 50° C.), yielding 0.007 gof compound 30.

Compounds identified as No. 31 to No. 58 in the following table F-1 weresimilarly prepared while using the same experimental procedure andreplacing 1,2-diaminoethane by the appropriate reactive diamine.

EXAMPLE B.3

NMP (2 ml) was added to resin (2-a) (0.00014 mol). BINAP (0.00014 mol)and sodium tert-butoxide (0.00252 mol) were added portionwise.4-Amino-1-tert-butoxycarbonylpiperidine (0.0021 mol) in NMP (1 ml) wasadded and the mixture was shaken for 1 hour under nitrogen. Pd₂(dba)₃(0.000028 mol) in NMP (1 ml) was added and the reaction mixture wasshaken for 18 hours at 105° C. The mixture was cooled, filtered and thefilter residue was washed with DMF-water 50-50, DMF (3×), water (3×),DMF (3×), CH₃OH (3×), DCM (3×), CH₃OH (3×) and DCM (3×). TMSOTf (1 M)and 2,6-lutidine (1.5 M) in DCM (3 ml) was added and the mixture wasshaken for 2 hours at room temperature. The mixture was filtered, washedwith DCM (3×), and methanol (4 ml) was added. The mixture was shaken forone hour at room temperature, filtered and the filter residue was washedwith DCM (3×), CH₃OH (3×), DCM (3×), CH₃OH (3×), DCM (3×), CH₃OH (3×),and once with NMP. NMP (3 ml) was added. Ethyl 2-bromo-2-phenylacetate(0.0007 mol) in NMP (1 ml) was added. DIPEA (0.3 ml) was added and thereaction mixture was shaken for 20 hours at room temperature. Thereaction mixture was filtered, washed three times with DMF, 3× withwater, 3×DMF, 3×CH₃OH, 3×DCM, 3×CH₃OH and 3×DCM. TFA/TIS/DCM (49:2:49)(4 ml) was added and the mixture was shaken for one hour at roomtemperature, then filtered. More TFA/TIS/DCM (49:2:49) (2 ml) was addedand the mixture was shaken for 30 minutes, then filtered, and washedwith DCM (2 ml). The filtrates were blown dry under nitrogen at 50° C.The residue was purified by HPLC over Purospher Star RP-18 (20 g, 5 μm;eluent: ((0.5% NH₄OAc in H₂O)/CH₃CN 90/10)/CH₃OH/CH₃CN (0 min) 75/25/0,(10.00 min) 0/50/50, (16.00 min) 0/0/100, (18.10-20 min) 75/25/0). Thedesired fractions were collected and the organic solvent was evaporated.The aqueous concentrate was treated with an aqueous Na₂CO₃ solution,then extracted with DCM. The extract was separated and the filtrateswere blown dry under nitrogen at 50° C. The residue was dried further(vacuum, 55° C.), yielding 0.007 g of compound 59.

Compounds identified as No. 60 to No. 96 in the following table F-1 weresimilarly prepared while using the same experimental procedure andreplacing 4-amino-1-tert-butoxycarbonylpiperidine by the appropriatereactive amine.

EXAMPLE B.4

Resin (2-b) (0.00014 mmol) was washed with NMP (2 ml). BINAP (0.00014mol) and sodium tert-butoxide (0.00252 mol) were added.4-Amino-1-tert-butoxycarbonylpiperidine (0.0021 mol) in NMP (1 ml) wasadded. NMP (3 ml) was added and the mixture was shaken for 1 hour underargon. Pd₂(dba)₃ (0.000028 mol) in NMP (1 ml) was added and the reactionmixture was shaken for 18 hours at 105° C. The mixture was cooled,filtered and the filter residue was washed with DMF, DMF-water 50-50,DMF (3×), water (3×), DMF (3×), CH₃OH (3×), DCM (3×), CH₃OH (3×) and DCM(3×). TMSOTf (1 M) and 2,6-lutidine (1.5 M) in DCM (3 ml) was added andthe mixture was shaken for 2 hours at room temperature. The mixture wasfiltered, washed with DCM (3×), CH₃OH (3×), DCM (3×), CH₃OH (3×), DCM(3×), CH₃OH (3×), then with NMP (2×). NMP (3 ml) was added. Methyl2-bromo-2-phenylacetate (0.160 g) in NMP (1 ml) was added. DIPEA (0.3ml) was added. The reaction mixture was shaken for 20 hours at roomtemperature, filtered, washed with DMF, then DMF-water 50-50, then withDMF (3×), water (3×), DMF (3×), CH₃OH (3×), DCM (3×), CH₃OH (3×), andDCM (3×). TFA/TIS/DCM (49:2:49) (4 ml) was added and the mixture wasshaken for one hour, then filtered. More TFA/TIS/DCM (49:2:49) (2 ml)was added and the reaction mixture was shaken for 30 minutes, thenfiltered. The filtrates were blown dry under nitrogen at 50° C. Theresidue was purified by HPLC over Purospher Star RP-18 (20 g, 5 μm;eluent: ((0.5% NH₄OAc in water)/CH₃CN 90/10)/CH₃OH/CH₃CN (0 min)75/25/0, (10.00 min) 0/50/50, (16.00 min) 0/0/100, (18.10-20 min)75/25/0). The desired fractions were collected and the organic solventwas evaporated. The aqueous concentrate was treated with an aqueousNa₂CO₃ solution, then extracted with DCM. The extract was separated andthe filtrates were blown dry under nitrogen at 50° C. The residue wasdried further (vacuum, 50° C.), yielding 0.031 g of compound 97.

Compounds identified as No. 98 to No. 136 in the following table F-1were similarly prepared while using the same experimental procedure andreplacing 4-amino-1-tert-butoxycarbonylpiperidine by the appropriatereactive amine.

EXAMPLE B.5

A mixture of intermediate (3) (0.006 mol), methyl2-bromo-2-phenylacetate (0.011 mol), triethylamine (1.6 ml) andtetrabutylammonium iodide (0.001 mol) in THF (20 ml) was stirred at roomtemperature for 8 hours. Water was added. The mixture was extracted withethyl acetate. The organic layer was separated, dried, filtered, and thesolvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 98.5/1.5) andcrystallized from diethyl ether, yielding compound (137), mp. 142° C.

Table F-1 lists the compounds that were prepared according to one of theabove Examples. The following abbreviations were used in the tables:.C₂HF₃O₂ stands for the trifluoroacetate salt.

TABLE F-1

Co. No. 1; Ex. B.1

Co. No. 2; Ex. B.1

Co. No. 3; Ex. B.1

Co. No. 4; Ex. B.1

Co. No. 5; Ex. B.1

(TRANS); Co. No. 6; Ex. B.1

Co. No. 7; Ex. B.1

Co. No. 8; Ex. B.1

Co. No. 9; Ex. B.1

Co. No. 10; Ex. B.1

(TRANS); Co. No. 11; Ex. B.1

Co. No. 12; Ex. B.1

Co. No. 13; Ex. B.1

Co. No. 14; Ex. B.1

Co. No. 15; Ex. B.1

Co. No. 16; Ex. B.1

(TRANS); Co. No. 17; Ex. B.1

Co. No. 18; Ex. B.1

Co. No. 19; Ex. B.1

Co. No. 20; Ex. B.1

Co. No. 21; Ex. B.1

Co. No. 22; Ex. B.l

(TRANS); Co. No. 23; Ex. B.1

Co. No. 24; Ex. B.1

Co. No. 25; Ex. B.1

Co. No. 26; Ex. B.1

Co. No. 27; Ex. B.1

Co. No. 28; Ex. B.1

(TRANS); Co. No 29; Ex. B.1

Co. No. 30; Ex. B.2

Co. No. 31; Ex. B.2

Co. No. 32; Ex. B.2

Co. No. 33; Ex. B.2

Co. No. 34; Ex. B.2

Co. No. 35; Ex. B.2

Co. No. 36; Ex. B.2

Co. No. 37; Ex. B.2

Co. No. 38; Ex. B.2

Co. No. 39; Ex. B.2

Co. No. 40; Ex. B.2

Co. No. 41; Ex. B.2

Co. No. 42; Ex. B.2

Co. No. 43; Ex. B.2

Co. No. 44; Ex. B.2

Co. No. 45; Ex. B.2

Co. No. 46; Ex. B.2

Co. No. 47; Ex. B.2

Co. No. 48; Ex. B.2

Co. No. 49; Ex. B.2

(TRANS); Co. No. 50; Ex. B.2

Co. No. 51; Ex. B.2

Co. No. 52; Ex. B.2

Co. No. 53; Ex. B.2

(TRANS); Co. No. 54, Ex. B.2

Co. No. 55; Ex. B.2

(TRANS); Co. No. 56; Ex. B.2

Co. No. 57; Ex. B.2

(TRANS); Co. No. 58; Ex. B.2

Co. No. 59; Ex. B.3

Co. No. 60; Ex. B.3

Co. No. 61; Ex. B.3

Co. No. 62; Ex. B.3

Co. No. 63; Ex. B.3

Co. No. 64; Ex. B.3

Co. No. 65; Ex. B.3

Co. No. 66; Ex. B.3

Co. No. 67; Ex. B.3

Co. No. 68; Ex. B.3

Co. No. 69; Ex. B.3

Co. No. 70; Ex. B.3

Co. No. 71; Ex. B.3

Co. No. 72; Ex. B.3

Co. No. 73; Ex. B.3

Co. No. 74; Ex. B.3

Co. No. 75; Ex. B.3

Co. No. 76; Ex. B.3

Co. No. 77; Ex. B.3

Co. No. 78; Ex. B.3

Co. No. 79; Ex. B.3

Co. No. 80; Ex. B.3

Co. No. 81; Ex. B.3

Co. No. 82; Ex. B.3

Co. No. 83; Ex. B.3

Co. No. 84; Ex. B.3

Co. No. 85; Ex. B.3

Co. No. 86; Ex. B.3

Co. No. 87; Ex. B.3

Co. No. 88; Ex. B.3

Co. No. 89; Ex. B.3

Co. No. 90; Ex. B.3

Co. No. 91; Ex. B.3

Co. No. 92; Ex. B.3

Co. No. 93; Ex. B.3

Co. No. 94; Ex. B.3

Co. No. 95; Ex. B.3

Co. No. 96; Ex. B.3

Co. No. 97; Ex. B.4

Co. No. 98; Ex. B.4

Co. No. 99; Ex. B.4

Co. No. 100; Ex. B.4

Co. No. 101; Ex. B.4

Co. No. 102; Ex. B.4

Co. No. 103; Ex. B.4

Co. No. 104; Ex. B.4

Co. No. 105; Ex. B.4

Co. No. 106; Ex. B.4

Co. No. 107; Ex. B.4

Co. No. 108; Ex. B.4

Co. No. 109; Ex. B.4

Co. No. 110; Ex. B.4

Co. No. 111; Ex. B.4

Co. No. 112; Ex. B.4

Co. No. 113; Ex. B.4

Co. No. 114; Ex. B.4

Co. No. 115; Ex. B.4

Co. No. 116; Ex. B.4

Co. No. 117; Ex. B.4

Co. No. 118; Ex. B.4

Co. No. 119; Ex. B.4

Co. No. 120; Ex. B.4

Co. No. 121; Ex. B.4

Co. No. 122; Ex. B.4

Co. No. 123; Ex. B.4

Co. No. 124; Ex. B.4

Co. No. 125; Ex. B.4

Co. No. 126; Ex. B.4

Co. No. 127; Ex. B.4

Co. No. 128; Ex. B.4

Co. No. 129; Ex. B.4

Co. No. 130; Ex. B.4

Co. No. 131; Ex. B.4

Co. No. 132; Ex. B.4

Co. No. 133; Ex. B.4

Co. No. 134; Ex. B.4

Co. No. 135; Ex. B.4

Co. No. 136; Ex. B.4

Co. No. 137; Ex. B.5C. Pharmacological Examples.C.1. Quantification of the Secretion of ApoB.

HepG2 cells were cultured in 24-well plates in MEM Rega 3 containing 10%fetal calf serum. At 70% confluency, the medium was changed and the testcompound or carrier (DMSO, 0.4% final concentration) was added. After 24hours of incubation, the medium was transferred to Eppendorf tubes andcleared by centrifugation. A sheep antibody directed against either apoBwas added to the supernatant and the mixture was kept at 8° C. for 24hours. Then, rabbit anti-sheep antibody was added and the immune complexwas allowed to precipitate for 24 hours at 8° C. The immunoprecipitatewas pelleted by centrifugation for 25 minutes at 1320 g and washed twicewith a buffer containing 40 mM Mops, 40 mM NaH₂PO₄, 100 mM NaF, 0.2 mMDTT, 5 mM EDTA, 5 mM EGTA, 1% Triton-X-100, 0.5% sodium deoxycholate(DOC), 0.1% SDS, 0.2 μM leupeptin and 0.2 μM PMSF. Radioactivity in thepellet was quantified by liquid scintillation counting.

Resulting IC₅₀ values are enumerated in Table C.1.

TABLE C.1 pIC50 values (= −log IC₅₀ value) Compound number pIC50 1 7.1492 6.499 3 6.116 4 7.007 5 5.992 6 5.683 7 6.482 8 6.888 9 6.247 10 6.02311 5.862 12 6.162 13 6.312 14 6.028 15 6.121 16 5.899 17 6.092 18 >7.52319 6.641 20 5.715 21 6.296 22 5.987 23 5.805 24 6.766 25 6.023 26 5.70627 6.204 28 5.826 29 6.123 98 5.801 100 7.38 101 7.388 102 <5.523 1035.796 104 >7.523 105 6.737 106 5.523 107 5.805 108 7.161 109 6.823 1105.93 111 6.458 112 7.404 113 7.97 114 5.583 115 6.023 116 7.023 117>7.523C.2. MTP Assay

MTP activity was measured using an assay similar to one described by J.R. Wetterau and D. B. Zilversmit in Chemistry and Physics of Lipids, 38,205-222 (1985). To prepare the donor and acceptor vesicles, theappropriate lipids in chloroform were put into a glass test tube anddried under a stream of N₂. A buffer containing 15 mM Tris-HCl pH 7.5, 1mM EDTA, 40 mM NaCl, 0.02% NaN₃ (assay buffer) was added to the driedlipid. The mixture was vortexed briefly and the lipids were then allowedto hydrate for 20 min on ice. Vesicles were then prepared by bathsonication (Branson 2200) at room temperature for maximum 15 min.Butylated hydroxytoluene was included in all vesicle preparations at aconcentration of 0.1%. The lipid transfer assay mixture contained donorvesicles (40 nmol phosphatidylcholine, 7.5 mol % of cardiolipin and 0.25mol % glycerol tri [1-¹⁴C]-oleate), acceptor vesicles (240 mmolphosphatidylcholine) and 5 mg BSA in a total volume of 675 μl in a 1.5ml microcentrifuge tube. Test compounds were added dissolved in DMSO(0.13% final concentration). After 5 minutes of pre-incubation at 37°C., the reaction was started by the addition of MTP in 100 μl dialysisbuffer. The reaction was stopped by the addition of 400 μl DEAE-52cellulose pre-equilibrated in 15 mM Tris-HCl pH 7.5, 1 mM EDTA, 0.02%NaN₃ (1:1, vol/vol). The mixture was agitated for 4 min and centrifugedfor 2 min at maximum speed in an Eppendorf centrifuge (4° C.) to pelletthe DEAE-52-bound donor vesicles. An aliquot of the supernatantcontaining the acceptor liposomes was counted and the [¹⁴C]-counts wereused to calculate the percent triglyceride transfer from donor toacceptor vesicles.

1. A compound of formula (I)

the N-oxides, the pharmaceutically acceptable acid addition salts andthe stereochemically isomeric forms thereof, wherein p¹, p² and p³ areintegers each independently from 1 to 3; each R¹ is independentlyselected from the group consisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkyloxy,halo, hydroxy, mercapto, cyano, nitro, C₁₋₄alkylthio, polyhaloC₁₋₆alkyl,amino, C₁₋₄alkylamino and di(C₁₋₄alkyl)amino; each R² is independentlyselected from the group consisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkyloxy,halo, and trifluoromethyl; R³ is hydrogen or C₁₋₄alkyl; each R⁴ isindependently selected from the group consisting of hydrogen, C₁₋₄alkyl,C₁₋₄alkyloxy, halo, and trifluoromethyl; Z is a bivalent radical offormula

 wherein m and m′ are integers from 1 to 3; R⁵ is hydrogen, C₁₋₆alkyl oraryl; X¹ is selected from the group consisting of CH, N and an sp²hybridized carbon atom; A represents a bond, or C₁₋₆alkanediyloptionally substituted with one or two groups selected from the groupconsisting of aryl, heteroaryl and C₃₋₁₀cycloalkyl; B representshydrogen; C₁₋₁₀alkyl; or aryl or heteroaryl each optionally substitutedwith a group selected from halo, cyano, nitro, C₁₋₄alkyloxy, amino,C₁₋₁₀alkylamino, di(C₁₋₁₀alkyl)amino, C₁₋₁₀acyl, C₁₋₁₀alkylthio,C₁₋₁₀alkoxycarbonyl, C₁₋₁₀alkylaminocarbonyl anddi(C₁₋₁₀alkyl)aminocarbonyl; arylC₁₋₁₀alkyl; heteroarylC₁₋₁₀alkyl;C₃₋₁₀cycloalkyl; polyhaloC₁₋₆alkyl; C₃₋₆alkenyl; C₃₋₆alkynyl; NR⁷R⁸; orOR⁹; wherein R⁷ and R⁸ each independently represent hydrogen;C₁₋₁₀alkyl; or aryl or heteroaryl each optionally substituted with agroup selected from halo, cyano, C₁₋₄alkyloxy, amino, C₁₋₁₀alkylamino,di(C₁₋₁₀alkyl)amino, C₁₋₁₀acyl, C₁₋₁₀alkylthio, C₁₋₁₀alkylaminocarbonyland di(C₁₋₁₀alkyl)aminocarbonyl; arylC₁₋₁₀alkyl; heteroarylC₁₋₁₀alkyl;C₃₋₁₀cycloalkyl; C₇₋₁₀polycycloalkyl; polyhaloC₁₋₆alkyl; C₃₋₈alkenyl;C₃₋₈alkynyl, fused benzo-C₅₋₈cycloalkyl; or R⁷ and R⁸ taken togetherwith the nitrogen atom to which they are attached form a saturatedheterocyclic radical having from 4 to 8 carbon atoms; and wherein R⁹represents C₁₋₁₀alkyl; or aryl or heteroaryl each optionally substitutedwith a group selected from halo, cyano, nitro, C₁₋₄alkyloxy, amino,C₁₋₁₀alkylamino, di(C₁₋₁₀alkyl)amino, C₁₋₁₀acyl, C₁₋₁₀alkylthio,C₁₋₁₀alkylaminocarbonyl and di(C₁₋₁₀alkyl)aminocarbonyl; arylC₁₋₁₀alkyl;heteroarylC₁₋₁₀alkyl; C₃₋₁₀cycloalkyl; C₇₋₁₀polycycloalkyl;polyhaloC₁₋₆alkyl; C₃₋₈alkenyl; C₃₋₈alkynyl; or fusedbenzoC₅₋₈cycloalkyl.
 2. A compound as claimed in claim 1 wherein R¹ ishydrogen or trifluoromethyl; R², R³ and R₄ are hydrogen; and Z is abivalent radical of formula (a-2) wherein X¹ is nitrogen, m and m′ arethe integer 1, and R⁵ is hydrogen or methyl.
 3. A compound as claimed inclaim 1 wherein R₁ is hydrogen or trifluoromethyl; R², R³ and R⁴ arehydrogen; and Z is a bivalent radical of formula (a-2) wherein X¹ isnitrogen, m is the integer 2, m′ is the integer 1, and R⁵ is hydrogen ormethyl.
 4. A compound as claimed in claim 1 wherein R¹ is hydrogen ortrifluoromethyl; R², R³ and R⁴ are hydrogen; and R⁵ is hydrogen ormethyl.
 5. A compound as claimed in claim 1 wherein A is C₁₋₆alkanediylsubstituted with phenyl and B is C₁₋₄alkyloxy, or C₁₋₁₀alkylamino.
 6. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a therapeutically active amount of a compound as claimed inclaim 1.